TMEM184B REDUCTION DISRUPTS NEUROMUSCULAR JUNCTION MAINTENANCE VIA THE ENDOSOMAL TRAFFICKING PATHWAY

Abstract

The Neuromuscular Junction (NMJ) is a complex synapse critical for skeletal muscle contraction. NMJ structure and function are crucial components to preserving motor neuron longevity. Motor neuron impairment is a pathological hallmark in various degenerative disorders. Our lab’s research seeks to identify factors critical for NMJ maintenance. We investigate TMEM184B, an endosomal membrane protein involved in NMJ structure and function. Tmem184b homozygous mutant mice show accumulations of multilamellar compartments and motor weakness. Here we specifically evaluated the effect of heterozygous mutation on axon and NMJ pathology using mice in which motor neurons are genetically labeled (Thy1-YFP). We found that heterozygous mice are substantially more likely to develop pre-synaptic swellings compared to wild-type mice, suggesting a dose-dependent effect on nerve terminal morphology. We identified binding partners of TMEM184B in human cells using immunoprecipitation and mass spectrometry. Additionally, we have evaluated the colocalization of TMEM184B with markers of early and late endosomes using transfected HEK293T cells. Our results suggest that TMEM184B interacts with proteins critical for endolysosomal flux. Our results are also consistent with the idea that Tmem184b heterozygous mutations may play a role in exacerbating motor neuron pathology in the context of diseases.